Piperidine derivatives and cosmetic compositions thereof

ABSTRACT

The present invention provides piperidine derivatives of formula (I): 
                         
salts and optical isomers thereof and cosmetic compositions containing them.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of prior U.S. patentapplication Ser. No. 11/629,196, filed Jul. 16, 2007, the disclosure ofwhich is incorporated herein by reference in its entirety. The parentapplication is the National Stage of PCT/EP05/06333, filed May 16, 2005,the disclosure of which is incorporated herein by reference in itsentirety. The parent application claims priority to French ApplicationNo. 04/51273, filed Jun. 15, 2004, and U.S. Provisional PatentApplication 60/582,809, filed Jun. 28, 2004, the disclosures of whichare incorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the cosmetic use, as an agent forcombating wrinkles, especially expression wrinkles, and/or fordecontracting the skin and/or relaxing the features, of at least onepiperidine derivative of given formula. The invention also relates to anovel family of piperidine derivatives and to cosmetic compositionscontaining them.

2. Description of the Related Art

Women, and even men, currently have a tendency to wish to look youthfulfor as long as possible and consequently seek to fade out the age markson the skin, which are reflected in particular by wrinkles and finelines. In this respect, advertising and the fashion world report aboutproducts intended to keep the skin radiant and wrinkle-free for as longas possible, which are signs of youthful skin, and all the more so sincethe physical appearance acts on the psyche and/or on the morale.

Hitherto, wrinkles and fine lines were treated using cosmetic productscontaining active agents acting on the skin, for example by improvingits cell renewal or alternatively by promoting the synthesis, or bypreventing the degradation of the elastic fibres thereof of which skintissue is composed.

Although these treatments make it possible to act on the wrinkles andfine lines caused by chronological or intrinsic ageing, and also onthose caused by photoageing, they have no effect on expression wrinkles,which require an intervention on the muscular contractile component (viamuscle-relaxing agents) or dermal contractile component (viadermo-decontracting agents) of wrinkles.

Specifically, expression wrinkles are the result of mechanisms differentfrom those that generate the wrinkles caused by ageing.

Specifically, they are produced due to the effect of the strain exertedon the skin by the skin muscles that allow facial expressions. Dependingon the shape of the face, the frequency of facial expressions andpossible tics, they may appear even from childhood. Age, and alsocertain environmental factors such as exposure to sunlight, do not playa part in generating them, but may make them deeper and permanent.

Expression wrinkles are characterized by the presence of grooves aroundthe orifices formed by the nose (nasal grooves), the mouth (perioralwrinkles and “sour-face” wrinkles) and the eyes (crow's-feet wrinkles),around which are the skin muscles, and also between the eyebrows(glabella wrinkles or lion wrinkles) and on the forehead.

Hitherto, the only means commonly used for acting on expression wrinklesis botulinum toxin, which is especially injected into the wrinkles ofthe glabella which are wrinkles between the eyebrows (see J. D.Carruters et al., J. Dermatol. Surg. Oncol., 1992, 18, pp. 17-21).

The Applicant has also proposed various compounds capable of affording amuscle-relaxing effect when they are applied topically to the skin, thusmaking it possible to act on expression wrinkles via another route.Among these compounds that may especially be mentioned are antagonistsof the receptors associated with the calcium channels, such as verapamil(FR-2 793 681), and in particular manganese and its salts (FR-2 809 005)and alverine (FR-2 798 590); and agonists of the receptors associatedwith the chlorine channels, including glycine (EP-0 704 210) and certainextracts of Iris pallida (FR-2 746 641); and sapogenins (EP-1 352 643).

Along with these muscle-relaxing agents, the Applicant has describedvarious dermo-decontracting compounds and in particular amine compounds(EP-1 405 633).

However, there is still a need for other effective compounds forsmoothing or fading out wrinkles, in particular expression wrinkles.

The Applicant has now discovered, surprisingly, that certain piperidinederivatives can satisfy this need.

Some of these compounds have already been described as antibacterialagents (Varma, Rajendra S. et al., Synthesis and antibacterial activityof certain beta-aminoketones, Journal of Pharmaceutical Sciences, 57(7),1251-3, 1968) or as narcotic antagonists and anti-inflammatory agents inparticular (Collino F. et al., Mannich ketobases withnarcotic-antagonistic activity, Bolletino Chimico Fazrmaceutico, SocietaEditoriale Farmaceutica, Milano, Vol. 122, No. 8, August 1983). Yetothers have been described as chemokine receptor modulators, which mayespecially be used topically to treat various skin conditions such aspsoriasis (WO 2004/056809).

However, it has never yet been suggested to use these compounds forcosmetic purposes, in particular for smoothing out wrinkles.

One subject of the present invention is thus the cosmetic use, as anagent for combating wrinkles, especially expression wrinkles, and/or fordecontracting the skin and/or relaxing the features, of at least onepiperidine derivative chosen from the compounds of formula (I):

in which:

R denotes a halogen or a radical chosen from: a C₁-C₆ alkyl radical, agroup OR′, a group NR′R″, a CF₃ group, a group NHCOR′R″ or a groupCONR′R″;

X denotes an oxygen atom, a hydroxyl group or a hydrogen atom;

Y denotes a phenyl group optionally substituted with at least oneradical R as defined above; or a linear or branched C₁-C₁₇ alkyl oralkenyl radical, optionally substituted with at least one group OR′,COOR′, ═O, NR′R″, NHCOR′R″ or CONR′R″ or with a phenyl group optionallysubstituted with at least one radical R as defined above;

Z denotes a hydrogen atom or a phenyl group optionally substituted withat least one radical R as defined above; or a linear or branched C₁-C₁₇alkyl or alkenyl radical, optionally substituted with at least one groupOR′, COOR′, ═O, NR′R″, NHCOR′R″ or CONR′R″;

it being understood that when X and Z each denote a hydrogen atom andwhen Y denotes an alkyl or alkenyl radical, the said radical contains atleast 5 carbon atoms,

in which R′ and R″ denote, independently of each other, a hydrogen atomor a C₁-C₆ alkyl radical,

m ranges from 0 to 5;

n ranges from 2 to 5;

p is 0 when X is an oxygen atom and 1 in the other cases,

and the salts and optical isomers thereof.

A subject of the invention is also a cosmetic process for treatingwrinkled skin, in particular skin of the face and/or the forehead,comprising the topical application to the said skin of a compositioncomprising, in a physiologically acceptable medium, at least onepiperidine derivative as defined above.

Insofar as some of the piperidine derivatives of formula (I) are novelper se, a subject of the invention is also these novel piperidinederivatives, characterized in that they are chosen from the compounds offormula (I) above and the salts and optical isomers thereof, it beingunderstood that when Y denotes an optionally substituted phenyl group, Xis a hydrogen atom.

A subject of the invention is also a composition containing, in aphysiologically acceptable medium, at least one of the novel piperidinederivatives as defined above.

In formula (I) the alkyl groups may be chosen especially, depending onthe case, from the following groups: methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl, dodecyl, myristyl and palmityl.

In addition, in the context of this application, the term “alkenyl”means radicals possibly comprising one or more conjugated ornon-conjugated double bonds. They may be chosen especially, depending onthe case, from the following groups: vinyl, allyl, butenyl or pentenyl.

Radicals R that are preferred in formula (I) are methoxy (OCH₃) andtrifluoromethyl (CF₃) radicals.

Salts of the compound of formula (I) that may be mentioned include thesalts obtained by addition of the compound of formula (I) to a mineralacid, chosen especially from hydrochloric acid, sulfuric acid andphosphoric acid, or to an organic acid, chosen in particular from aceticacid, propionic acid, succinic acid, fumaric acid, lactic acid, glycolicacid, citric acid and tartaric acid.

Preferably, the piperidine derivative according to the invention is suchthat m ranges from 0 to 3 and m is preferably equal to 0, and/or n isequal to 2 or 3 and n is preferably equal to 3.

In addition, according to a first advantageous embodiment of theinvention:

-   -   X is a hydrogen atom,    -   Y is a phenyl group,    -   m is equal to 0,    -   n is equal to 3,    -   p is equal to 1, and    -   Z is a hydrogen atom.

According to a second advantageous embodiment of the invention:

-   -   X is an oxygen atom,    -   Y is a linear or branched C₁-C₁₀ alkyl radical,    -   m is equal to 0,    -   n is equal to 3, and    -   p is equal to 0.

According to a third advantageous embodiment of the invention:

-   -   X is a hydroxyl group,    -   Y is a linear or branched C₁-C₁₀ alkyl radical,    -   m is equal to 0,    -   n is equal 3,    -   p is equal to 1, and    -   Z is a linear or branched C₁-C₁₀ alkyl radical.

In these second and third embodiments of the invention, the alkylradicals are preferably linear alkyl radicals. They preferably containfrom 3 to 7 carbon atoms and preferentially 5 carbon atoms.

The compounds of formula (I) may be prepared especially according to thefollowing reaction scheme:

by reaction of the substituted piperidine A (1 eq) with 1 equivalent ofα,β-unsaturated ketone in ethanol, at room temperature. The product Bmay be worked up and purified on a column of silica. Alternatively,product A (1 eq) may be reacted with the corresponding halo or sulfonateradical (1 eq) in the presence of K₂CO₃ in refluxing acetonitrileovernight. The product obtained B′ may be worked up and purified on acolumn of silica.

To obtain C, 1 equivalent of metallic derivative Zp (organomagnesium,organolithium or organozinc agent) may be reacted with 1 equivalent ofcompound B, in anhydrous THF, under nitrogen, at room temperature. Theproduct C thus obtained may be worked up and purified on a column ofsilica.

The amount of piperidine derivative that may be used according to theinvention obviously depends on the desired effect and may thus varywithin a wide range.

To give an order of magnitude, these derivatives may be used in anamount representing from 0.01% to 10% of the total weight of thecomposition, preferably in an amount representing from 0.05% to 5% ofthe total weight of the composition and more preferably in an amountrepresenting from 0.1% to 2% of the total weight of the composition.

The composition used according to the invention is suitable for topicalapplication to the skin and thus contains a physiologically acceptablemedium, i.e. a medium that is compatible with the skin and optionallywith its integuments (eyelashes, nails and hair) and/or mucousmembranes. This medium is advantageously cosmetically acceptable, i.e.it does not cause any itching, stinging or redness liable to put theuser off the composition, and it has a pleasant appearance, odour andfeel.

This composition may be in any presentation form normally used incosmetics, and it may especially be in the form of an optionally gelledsolution, a dispersion of the lotion type, optionally a two-phaselotion, an emulsion obtained by dispersing a fatty phase in an aqueousphase (O/W emulsion) or conversely (W/O emulsion), or a triple emulsion(W/O/W or O/W/O emulsion) or a vesicular dispersion of ionic and/ornonionic type. These compositions are prepared according to the usualmethods. A composition in the form of an oil-in-water emulsion ispreferably used according to this invention.

This composition may be more or less fluid and may have the appearanceof a white or coloured cream, an ointment, a milk, a lotion, a serum, apaste or a mousse. It may optionally be applied in the form of anaerosol. It may also be in solid form, in particular in the form of astick. It may be used as a care product, and/or as a makeup product forthe skin.

In a known manner, the composition used according to the invention mayalso contain adjuvants that are common in cosmetics, such as hydrophilicor lipophilic gelling agents, hydrophilic or lipophilic active agents,preserving agents, antioxidants, solvents, fragrances, fillers,screening agents, pigments, odour absorbers and dyestuffs. The amountsof these various adjuvants are those conventionally used in the fieldunder consideration, and, for example, from 0.01% to 20% relative to thetotal weight of the composition. Depending on their nature, theseadjuvants may be introduced into the fatty phase, into the aqueousphase, or into lipid vesicles. In any case, these adjuvants, and alsothe proportions thereof, will be chosen so as not to harm the desiredproperties of the compounds according to the invention.

When the composition used according to the invention is an emulsion, theproportion of the fatty phase may range from 5% to 80% by weight andpreferably from 5% to 50% by weight relative to the total weight of thecomposition. The oils, emulsifiers and co-emulsifiers used in thecomposition in emulsion form are chosen from those conventionally usedin the field under consideration. The emulsifier and co-emulsifier arepresent in the composition in a proportion ranging from 0.3% to 30% byweight and preferably from 0.5% to 20% by weight relative to the totalweight of the composition.

As oils which may be used in the invention, mention may be made ofmineral oils (liquid petroleum jelly), oils of plant origin (avocado oilor soybean oil), oils of animal origin (lanolin), synthetic oils(perhydrosqualene), silicone oils (cyclomethicone) and fluoro oils(perfluoropolyethers). Fatty alcohols (cetyl alcohol), fatty acids andwaxes (carnauba wax or ozokerite) may also be used as fatty substances.

As examples of emulsifiers and co-emulsifiers that may be used in theinvention, mention may be made of fatty acid esters of polyethyleneglycol such as PEG-100 stearate, and fatty acid esters of glycerol suchas glyceryl stearate.

Hydrophilic gelling agents/thickeners that may be mentioned inparticular include carboxyvinyl polymers (carbomer), acrylic copolymerssuch as acrylate/alkylacrylate copolymers, polyacrylamides,polysaccharides, natural gums and clays, and lipophilic gellingagents/thickeners that may be mentioned include modified clays, forinstance bentones, metal salts of fatty acids and hydrophobic silica.

As active agents, it will be advantageous to introduce into thecomposition used according to the invention at least one compound chosenfrom: desquamating agents; moisturizers; depigmenting or propigmentingagents; antiglycation agents; NO-synthase inhibitors; agents forstimulating the synthesis of dermal or epidermal macromolecules and/orfor preventing their degradation; agents for stimulating theproliferation of fibroblasts and/or keratinocytes or for stimulating thedifferentiation of keratinocytes; other muscle-relaxing agents and/ordermo-decontracting agents; tensioning agents; antipollution agentsand/or free-radical scavengers; agents acting on the capillarycirculation; agents acting on the energy metabolism of cells; andmixtures thereof.

Examples of such additional compounds are: retinol and its derivativessuch as retinyl palmitate; ascorbic acid and its derivatives such asmagnesium ascorbyl phosphate and ascorbyl glucoside; tocopherol and itsderivatives such as tocopheryl acetate; nicotinic acid and itsprecursors such as nicotinamide; ubiquinone; glutathione and itsprecursors such as L-2-oxothiazolidine-4-carboxylic acid; plant extractsand especially plant proteins and hydrolysates thereof, and also planthormones; marine extracts such as algal extracts; bacterial extracts;sapogenins such as diosgenin and extracts of wild yam containing it;ceramides; hydroxy acids such as salicylic acid and5-n-octanoylsalicylic acid; resveratrol; oligopeptides andpseudodipeptides and acyl derivatives thereof; manganese and magnesiumsalts, in particular the gluconates; and mixtures thereof.

As mentioned previously, the composition according to the invention mayalso contain UVA-active and/or UVB-active photoprotective agents, in theform of organic or mineral compounds, the latter optionally being coatedto make them hydrophobic.

The organic photoprotective agents may be chosen especially from:anthranilates, in particular menthyl anthranilate; benzophenones, inparticular benzophenone-1, benzophenone-3, benzophenone-5,benzophenone-6, benzophenone-8, benzophenone-9, benzophenone-12 and,preferably, benzophenone-3 (oxybenzone) or benzophenone-4 (Uvinul MS40available from BASF); benzylidenecamphors, in particular3-benzylidenecamphor, benzylidenecamphorsulphonic acid, camphorbenzalkonium methosulphate, polyacrylamido-methylbenzylidenecamphor,terephthalylidenedicamphorsulphonic acid and, preferably,4-methylbenzylidenecamphor (Eusolex 6300 available from Merck);benzimidazoles, in particular benzimidazilate (Neo Heliopan AP availablefrom Haarmann & Reimer), or phenylbenzimidazolesulphonic acid (Eusolex232 available from Merck); benzotriazoles, in particular drometrizoletrisiloxane, or methylenebis-benzotriazolyltetramethylbutylphenol(Tinosorb M available from Ciba); cinnamates, in particular cinoxate,DEA methoxycinnamate, diisopropyl methylcinnamate, glycerylethylhexanoate dimethoxycinnamate, isopropyl methoxycinnamate, isoamylcinnamate and, preferably, ethocrylene (Uvinul N35 available from BASF),octyl methoxycinnamate (Parsol MCX available from Hoffmann La Roche), oroctocrylene (Uvinul 539 available from BASF); dibenzoylmethanes, inparticular butylmethoxydibenzoylmethane (Parsol 1789); imidazolines, inparticular ethylhexyl dimethoxybenzylidene dioxoimidazoline; PABAs, inparticular ethyl dihydroxypropyl PABA, ethylhexyldimethyl PABA, glycerylPABA, PABA, PEG-25 PABA and, preferably, diethylhexylbutamidotriazone(Uvasorb HEB available from 3V Sigma), ethylhexyltriazone (Uvinul T150available from BASF) or ethyl PABA (benzocaine); salicylates, inparticular dipropylene glycol salicylate, ethylhexyl salicylate,homosalate or TEA salicylate; triazines, in particular anisotriazine(Tinosorb S available from Ciba); drometrizole trisiloxane.

The mineral photoprotective agents preferably consist of zinc oxideand/or titanium dioxide, preferably of nanometric size, optionallycoated with alumina and/or stearic acid.

The composition according to the invention is advantageously intended tobe applied to the areas of the face and/or forehead that are marked withexpression wrinkles, and/or on individuals with expression wrinkles.

The wrinkles concerned are preferably those lying radially around themouth and/or the eyes, in particular the crow's-feet wrinkles, and/orlying on the forehead, in particular the “lion” wrinkle, located in theglabella, in between the eyebrows, and/or lying horizontally on theforehead.

The invention will now be illustrated with the non-limiting examplesthat follow. In these examples, the amounts are indicated as percentagesby weight.

EXAMPLES Example 1 Synthesis of 1,4-bis(3-phenylpropyl)piperidine

This compound was prepared according to the following reaction scheme:

3-Phenylpropylpiperidine (1 eq) was reacted with 3-phenylbromopropane (1eq) in the presence of K₂CO₃ in refluxing acetonitrile over night. Theproduct obtained was worked up and purified on a column of silica. The500 MHz ¹H NMR is in accordance with the expected structure.

Example 2 Synthesis of 1-[4-(3-phenylpropyl)piperidin-1-yl]octan-3-one

This compound was prepared according to the following reaction scheme:

1 equivalent of 4-(3-phenylpropyl)piperidine was reacted with 1equivalent of 1-octen-3-one in ethanol, at room temperature. The productwas worked up and purified on a column of silica. The results of the NMRand mass spectrometry analyses were in accordance with the expectedstructure.

Example 3 Synthesis of6-{2-[4-(3-phenylpropyl)piperidin-1-yl]ethyl}undecan-6-ol

This compound was prepared from the compound of Example 2, according tothe following reaction scheme:

1 equivalent of pentylmagnesium bromide was reacted with 1 equivalent ofthe compound obtained in Example 2, in anhydrous THF, under nitrogen, atroom temperature. The product thus obtained was worked up and purifiedon a column of silica. The results of the NMR and mass spectrometryanalyses were in accordance with the expected structure.

Example 4 Demonstration of the Muscle-Relaxing Effect of the DerivativesAccording to the Invention

The compound of Example 1 was tested on a model of nerve/musclecoculture, which makes it possible to recreate a motor arc byinnervating human striated muscle cells with explants of rat embryonicrachidian ganglia and spinal cord.

This test is predictive of an anti-wrinkle effect, as demonstrated bythe Applicant in the case of diazepam, which inhibited muscle fibrecontractions in this model and whose anti-wrinkle activity has beendemonstrated in vivo.

a) Protocol

Human muscle cells, obtained from samples of striated muscle fromhealthy donors, are inoculated into wells of cross section 1.8 cm²(24-well culture dishes). After culturing for ten days, these cells forma monolayer and fuse. At this stage, explants of embryonic spinal cordfrom a 13 day-old rat, containing the rachidian ganglia, are placed onthe culture.

The growth of the neurites is visible beyond the spinal cord explantafter one day of culture. The first contractions of the muscle fibresare observed after five to six days of coculture, and after three weeksall the muscle fibres in the region of the explants contract.

The cocultures are used after 21 days, when the muscle fibres arestriated and contain mature differentiated neuromuscular junctions.

A muscle fibre showing regular contractions (at least 60 contractionsper minute) is then selected from three different culture wells and thenumber of contractions is counted over 30 seconds. The test compound,diluted in DMSO, is then incubated for 60 seconds in these wells, at aconcentration of 10⁻⁵ M. At the end of incubation, the number ofcontractions is again counted over 30 seconds. The test is performed intriplicate.

b) Results

One minute after adding the test compound to the wells, the contractionsof the fibre represent only 55% of its contractions before addition ofthe compound.

This compound therefore inhibits striated muscle contractions and canthus be used to relax the features of the face and to smooth outexpression wrinkles.

Example 5 Cosmetic Composition

This composition is prepared in a conventional manner for a personskilled in the art. The amounts given in this example are indicated inweight percentages.

Compound of Example 1 0.10% Stearic acid 3.00% Mixture of glycerylmonostearate and 2.50% polyethylene glycol stearate (100 EO)Polyethylene glycol stearate (20 EO) 1.00% Cyclopentadimethylsiloxane10.00%  Fillers 3.00% Plant oils 7.00% Synthetic oils 6.00% Preservingagents 1.20% Oxyethylenated dimethylsiloxane (16 EO) 1.00% containingmethoxy end groups Silicone gum 0.20% Acrylic copolymer as an inverseemulsion 1.70% (Simulgel 600 from SEPPIC) Stearyl alcohol 1.00% Waterqs 100%

This cream is intended to be applied to the face and the forehead torelax the features and to decontract facial skin.

The invention claimed is:
 1. A piperidine compound or its salt, whereinthe piperidine compound is1-[4-(3-phenylpropyl)piperidin-1-yl]octan-3-one.
 2. A piperidinecompound or its salt, wherein the piperidine compound is6-{2-[4-(3-phenylpropyl)piperidin-1-yl]ethyl}undecan-6-ol.
 3. Acomposition, comprising: a physiologically acceptable medium and apiperidine compound, or its salt, according to claim
 1. 4. Thecomposition according to claim 3, further comprising at least oneadjuvant selected from the group of adjuvants consisting of ahydrophilic or lipophilic gelling agent, a hydrophilic or lipophilicactive agent, a preserving agent, an antioxidant, a solvent, afragrance, a filler, a screening agent, a pigment, a odor absorber and adyestuff.
 5. The composition according to claim 4, wherein thecomposition is an oil-in-water emulsion comprising a fatty phase.
 6. Thecomposition according to claim 5, wherein a content of the fatty phaseis from 5% to 80% by weight relative to the total weight of thecomposition.
 7. The composition according to claim 5, wherein theoil-in-water emulsion further comprises from 0.3% to 30% by weightemulsifiers and co-emulsifiers relative to the total weight of thecomposition.
 8. The composition according to claim 5, wherein theoil-in-water emulsion comprises at least one oil selected from the groupof oils consisting of a mineral oil, an oil of plant origin, an oil ofanimal origin, a synthetic oil, a silicone oil and a fluoro oil.
 9. Thecomposition according to claim 7, wherein the at least one emulsifierand co-emulsifier is selected from fatty acid esters of polyethyleneglycol and fatty acid esters of glycerol.
 10. A composition, comprising:a physiologically acceptable medium and a piperidine compound, or itssalt, according to claim
 2. 11. The composition according to claim 10,further comprising at least one adjuvant selected from the group ofadjuvants consisting of a hydrophilic or lipophilic gelling agent, ahydrophilic or lipophilic active agent, a preserving agent, anantioxidant, a solvent, a fragrance, a filler, a screening agent, apigment, a odor absorber and a dyestuff.
 12. The composition accordingto claim 10, wherein the composition is an oil-in-water emulsioncomprising a fatty phase.
 13. The composition according to claim 12,wherein a content of the fatty phase is from 5% to 80% by weightrelative to the total weight of the composition.
 14. The compositionaccording to claim 12, wherein the oil-in-water emulsion furthercomprises from 0.3% to 30% by weight emulsifiers and co-emulsifiersrelative to the total weight of the composition.
 15. The compositionaccording to claim 12, wherein the oil-in-water emulsion comprises atleast one oil selected from the group of oils consisting of a mineraloil, an oil of plant origin, an oil of animal origin, a synthetic oil, asilicone oil and a fluoro oil.
 16. The composition according to claim14, wherein the at least one emulsifier and co-emulsifier is selectedfrom fatty acid esters of polyethylene glycol and fatty acid esters ofglycerol.